DERIVATIVES OF 1,4,4a,9b-TETRAHYDRO-8,9b-DIMETHYL-2-PHENYL-1,4-ETHANOBENZOFURO {8 3,2-C{9 PYRIDINE-3(2H), 10-DIONE

ABSTRACT

This disclosure describes derivatives of 1,4,4a,9b-tetrahydro8,9b-dimethyl-2-phenyl-1,4-ethanobenzofuro(3,2-c) -pyridine-3(2H), 10-dione useful as antidepressant, anti-inflammatory, or analgetic agents.

United States Patent Morlock et al.

[ 1 June 27, 1972 Donald Albright; Leon Goldman, both of Nanuet, all ofNY.

[73] Assignee: American Cyanamid Company, Stamford,

Conn.

[22] Filed: May 4, 1970 211 AppLNo 34,614

[52] US. Cl ..260/293.55, 260/3265 CA, 424/267 [51 Int. Cl. ..C07d 99/04[58] Field of Search ..260/293.55

[56] References Cited OTHER PUBLICATIONS Plieninger et al., Ber. 97(3),667 and 6 73 (1964) Primary Examiner-Hem R. J iles Assistant ExaminerG.Thomas Todd Attorney'Edward A. Conroy, Jr.

57 ABSTRACT This disclosure describes derivatives of l,4,4a,9b-tet rahydro- 8 ,9b-dimethyl-2-phenyl-l ,4-ethanobenzofuro[ 3 ,2-cpyridine-3(2H),lO-dione useful as antidepressant, anti-inflammatory, oranalgetic agents.

9 Claims, No Drawings DlMETHYL-Z-PHENYL-l ,4-ETIMNOBENZOFURO [3,2-

CIPYRIDINE-SQH), lO-DIONE BRIEF SUMMARY OF THE INVENTION This inventionrelates to novel derivatives of '1,4,4a,-9b.-

I tetrahydro-S ,Qb-dimethyl-Z-phenyll ,4-ethanobenzofuro[ 3,2-

c]-pyridine-3(2I-I),l0-dione and to methods of preparing thesecompounds. The novel compounds of the present invention may berepresented by the following general formulae:

o A -NH-R,

wherein R is phenyl or p-bromophenyl, and R and R are the same and arephenyl or p-bromophenyl. Also included within the purview of the presentinvention are the 3-pyrr0lidine enamines of the carboxanilides (II)which are useful as intermediates in the preparation of thecarboxanilides (II).

DETAILED DESCRIPTION OF THE INVENTION Certain of the novel compounds ofthe present invention are active analgetics when measured by thewrithing syndrome test for analgetic activity as described by Siegmundet al., Proc. Soc. Exptl. Biol. Med, Vol. 9, p. 729 (1957), withmodifications. This method is based upon the reduction of the number ofwrithes following the intraperitoneal injection of l mg./kg. of bodyweight of phenyl-p-quinone in male Swiss Albino mice weighing 15-25grams per mouse. This syndrome is characterized by intermittentcontractions of the abdomen, twisting and turning of the trunk, andextension of the hind legs beginning 3 to 5 minutes after injection ofthe phenyl-pquinone. The test compound is administered orally to groupsof two mice each 30 minutes before injection of the phenyl-pquinone. Thetotal number of writhes exhibited by each group of mice is recorded fora3 minute period commencing minutes after injection of thephenyl-pquinone. A compound is considered active if it reduces the totalnumber of writhes in two test mice from a control value of approximately30 per air to a value of 18 or less. In a representative operation, thefollowing compounds of the present invention showed analgetic activitywhen tested by this procedure at the oral doses indicated in thefollowing table:

4a,9b-hexahydro-8 ,9b-climethyl-3 l 0- -dioxol,4-ethanobenzofuro[3,2-c]- pyridine-l l-carboxanilide4',4"-dibromo-2-(p-bromophenyl-1,2,3,4,4a,9b-hexahydro-8,9b-dimethyI-B-oxo- I 0-( l-pyrrolidinyl l,4-ethenobenzofuro[ 3 ,2-c lpyridine- 4,1 l-dicarboxanilide Theantidepressant properties of l,4,4a,9b-tetrahydro-8,9bdimethyl-2-phenyll,4-ethanobenzofuro[3,2-c]pyridine-3 (2H),-l0-dione are evident bymeasuring its ability to comteract a depression induced in animals bythe administration of tetrabenazine hexamate. Graded doses of thecompound are administered by intraperitoneal injection to groups ofmice, and this is followed by administering intraperitoneally a dose oftetrabenazine which is known to markedly depressthe exploratory behaviorof normal mice. The antidepressant treated groups show normalexploratory behavior, while the control groups, and groups treated withan inefiective antidepressant agent, do not show this normal exploratorybehavior, but show the well known profound depression induced bytetrabenazine. Theresults from several dose levels are used to establisheffective dose ranges. The antidepressant compound of this inventionshows its desirable properties by this procedure at dose levels whichproduce little or no untoward reactions such as ataxia or reducedspontaneous motor activity. In a representative operation,l,4,4a,9b-tetrahydro- 8,9b-dimethyl-2-phenyll ,4-ethanobenzofuro[ 3,2-c]pyridine- 3(2I-I), lO-dione showed antidepressant activity whentested by this procedure at a dose of 25 mg./kg. of body weight.

The novel compound 2-(p-bromophenyl)-l,4,4a,9btetrahydro-8,9b-dimethyll,4-ethanobenzofuro[ 3,2- I c]pyridine-3(2H),l0-dione possessesanti-inflammatory properties as determined by the carrageenin-inducedrat paw edema test as follows. In this test weanling Sherman strain ratsranging in weight from 50-55 grants are used and fed standard laboratorydiet ad libitum. Thetest compound is administered to the rats by gavage(250 milligrams per kilogram in a volume of 1.7 milliliters of bufi'eredaqueous starch) 1 hour prior to challenge with carrageenin. Thechallenge agent, carrageenin, is obtained from Marine Colloids, 2 EdisonPlace, Springfield, New Jersey and prepared as a sterile 1 percentsuspension in 0.09 percent aqueous sodium chloride. A volume of 0.05milliliter is injected using a 26 gauge needle into the plantar tissueof the right hind paw of treated and untreated rats. Measurements of thevolumes of the carrageenin inflamed right (challenged) paw and left(unchallenged) paw are determined 4 hours subsequent to the carrageeninchallenge. The method of determining paw volumes is carried outessentially as described by C. A. Winter, et al., in Proc. Soc. Exptl.Biol. Med. 1 11: 544-547 (1962) using mercury immersion. The differencesin volume of the two paws of each rat is considered to be the volume ofthe carrageenin induced edema. The mean edema volume of eight controlrats divided by the mean edema volume of two treated rats is calculatedand designated the C/T efficacy ratio. A compound is considered activein this test if the mean Cfl efficacy ratio of 2 consecutive tests isequal to or greater than 1.43. In a representative operation, the meanCfl efficacy ratio (four rats) of 2-(p-bromophenyl)- l,4,4a,9btetrahydro-8,9b-dimethyl-2-phenyl- 1 ,4- ethanobenzofuro[ 3,2]-pyridine-3( 2H), 1 O-dione above-described test was 3.48.

When mixed with suitable excipients or diluents, the compounds of thisinvention can be prepared as pills, capsules, tablets, powders,solutions, suspensions, and the like for unit dosage and to simplifyadministration.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 Preparation of 1-(4a,9b-dihydro-8,Qb-dimethyl-3-dibenzofuranyl)-pyrrolidine To a suspension of 2.00 g. of 4a,9b-dihydro-8,9b-dimethyldibenzofuran-3(4I- I)-one in 50 ml. of methanolwas added 3.4

in the ml. (2.9 g.) of pyrrolidine and the mixture was heated on a steambath for 10 minutes. The resulting clear yellow solution was allowed tostand at room temperature for 1 hour. The solvents were removed byevaporation under reduced pressure to yield a yellow syrupy residuewhich was redissolved in benzene and evaporated to dryness under reducedpressure to yield l-( 4a,9b-dihydro-8 ,9b-dirnethyl-3-dibenzofuranyl)pyrrolidine as a yellow syrup;

CHCI:

max.

6.05 and 6.14 ,i.

EXAMPLE 2 Preparation of l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxo- 2phcnyll l-pyrrolidinyl)- l ,4-ethenobenzofuro[ 3,2-c

lpyridinel l-carboxanilide and l,4,4a,9btetrahydro-8,9b-dimethyl-2-phenyll ,4-ethanobenzofuro[ 3 ,2-c]pyridine-3( 2H, 1 O-dione To 0.0221mole of l-(4a,9-dihydro-8,9b-dimethyl-3- dibenzofuranyl)pyrrolidine,prepared as in Example 1, in 100 ml. of dry benzene was added 2.40 ml.of phenyl isocyanate and the solution was allowed to stand at roomtemperature for 20 hours. The precipitate of4a,9b-dihydro-8,9b-dimethyl-3-l-pyrrolidinyl)-4-dibenzofurancarboxanilide which had separated wasremoved by filtration and the filtrate was evaporated to dryness underreduced pressure to yield a yellow gum as residue. The gum wascrystallized from ether to give 0.530 g. of crude product which wastriturated with benzene and filtered to yield 0.378 g. ofl,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxo-2-phenyl-10-(l-pyrrolidinyl)- l ,4-ethenobenzofuro[ 3 ,2-c]pyridine-l l-carboxanilidecolorless crystals, m.p. 2072 1 5 C.;

5.90, 5.98, 6.08 and 6.27 g. The ethereal mother liquor from above wasevaporated to dryness under reduced pressure to yield an orange gum.This was chromatographed on 100 g, of neutral alumina (Activity Ill).Elution with 180 ml. of benzene and evaporation of the eluate yielded0.890 g. of crude product, m.p. 1'8 3-l90 C. Crystallization fromabsolute ethanol gave 0.788 g. of 1,4,4a,-9b-tetrahydro-8,Qb-dimethyl-2-phenyll ,4-ethanobenzofuro[ 3 ,2-c]-pyridine-3( 2H), l 0 dione ascolorless crystals, m.p. l92-l94 C.;

5.74 and 5.93 p.

EXAMPLE 3 syrup as residue. Trituration of the syrup with anhydrousether yielded a tan percipitate which on filtration gave 2.30 g. ofcrude product. Trituration of the solid with hot benzene and filtrationyielded 0.524 g. of 4-bromo-2-(p-bromophenyl)- l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxol 0-( l-pyrrolidinyl)- l,4-ethenobenzofuro[ 3,2-c]pyridine-l l-carboxanilide as colorlesscrystals, m.p. 224-229 G; A333;

5.92, 6.08, and 6.28 pt. The ethereal mother liquor from above wasevaporated to dryness under reduced pressure to yield a dark red syrupas residue. The residue was chromatographed on 100 g. of neutral alumina(Activity Ill). Elution with benzene yielded, on evaporation underreduced pressure of the 150-320 ml. cut of the eluate, a colorless syrupwhich solidified on trituration with anhydrous ether. Filtration gave0.365 g. of 2-(p-bromophenyl)-l,4,4a,9b-tetrahydro-8,9b-

dimethyl-l ,4-ethanobenzofuro[ 3,2-c]pyridine-3( 2H), 1 0- dione'ascolorless crystals, m.p. l98204 C.;

use:

5.72 and 5.91

EXAMPLE 4.

Preparation of 4',4' '-dibromo-2-(p-bromophenyl)- l,2,3,4,4a,9b-

hexahydro-S,9b-dimethyl-3-oxol 0-( l-pyrrolidinyl)- l ,4- ethanoabenzofuro[3 ,2-c]pyridine-4,l l-dicarboxanilide To 0.0221 mole ofl-(4a,9b-dihydro-8,9b-dimethyl-3- dibenzofuranyl)pyrrolidine, preparedas in Example 1, in 100 ml. of dry benzene was added 9.20 g. ofp-bromophenyl isocyanate and allowed to stand at room temperature for 18hours. The resulting suspension was filtered to remove 6.56 g. of crude4'-bromo-4a,9b-dihydro-8,9b-dimethyl-B-(l-pyrrolidinyl)-4-dibenzofurancarboxanilide.The filtrate was evaporated under reduced pressure to yield a residualyellow syrup. This was tn'turated with ether and filtered to remove 1.71g. of 1,3,5-tris(p-bromophenyl)-s-triazine-2,4,6(l H,3H,5H)-trione,formed by self-condensation of the pbromophenyl isocyanate. The etherealfiltrate was evaporated to dryness under reduced pressure to yield a redsyrup which was chromatographed on 100 g. of neutral alumina (ActivityIII). Elution with 80 ml. of benzene yielded 0.560 g. of crude product.Trituration with hot ethanol .and filtration yielded 0.482 g. of4,4"-dibromo-2-(p-bromophenyl)-l,2,3,4,4a,9bhexahydro-8,9b-dimethyl-3-oxo l 0-( l-pyrrolidinyl)- l ,4-ethenobenzofuro[ 3 ,2 ]pyridine-4,1 l-dicarboxanilide colorlesscrystals, m.p. 224-225 C.;

KB Max.

5.90 and 6.00 p..

EXAMPLE 5 Preparation of l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3,10-dioxo- 2-phenyll ,4-ethanolbenzofuro[ 3 ,2-c ]pyridine-l l-carboxanilideA solution of 0.500 g. ofl,2,3,4,4a,9b-hexahydro-8,9bdimethyl-3oxo-2-phenyll 0-( l-pyrrolidinyl)-l ,4- ethenobenzofuro[ 3,2-c]pyridine-l l-carboxanilide in 50 ml. ofmethanol and 3 m1. of 1N hydrochloric acid was heated at reflux for 7hours. The solvents were removed by evaporation under reduced pressureto yield a semi-solid residue. Trituration with water yielded a solidwhich was collected by filtration to yield 0.424 g. of crude product.Recrystallization from ethanol yielded 0.230 g. ofl,2,3,4,4a,9b-hexahydro-8,9bdimethyl-3 l 0-dioxo-2-phenyll,4ethanobenzofuro[ 3 ,2-c] pyridine-l l-carboxanilide as colorlesscrystals, m.p. l82l 85 KB mi.

hexa- -hydrob-hexa hydro-8 ,9b-dimethyl-3 l Odioxo-l ,4-ethanobenzofuro[3 ,2-c ]pyridine-l l-carboxanilide A suspension of 0.813 g. of4'-bromo-2-(p-bromophenyl)- l,2,3,4,4u,9b-hexahydro-8,9b-dimethyl-3-oxol-( l -pyrrolidinyl l,4-ethenobenzofurol 3,2-c1pyridine-l l-carboxani lide in 70 ml. ofmethanol and 4 ml. of 1N hydrochloric acid was refluxed for 4% hours.The solvents were removed by evaporation under reduced pressure to yielda semi-solid as residue. The solid was collected by filtration andrecrystallized from chloroform-heptane to give 0.525 g. of4'-bromo-2-(pbromophenylyl ,2,3,-4,4a,9b-hexahydro-8,9b-dimethyl-3,10-dioxol ,4-ethanobenzofuro-[ 3 ,2-c]pyridine-l l-carboxanilide ascolorless crystals, m.p. 123-129 C.;

5.74 and 5.90

We claim:

1. A compound of the formula:

wherein R is selected from the group consisting of phenyl andp-bromophenyl.

2. The compound according to claim 1 wherein R is phenyl; l,4,4a,9b-tetrahydro-8,9b-dimethyl-2-phenyl-l ,4- ethanobenzofuro[ 3 ,2-c]pyridine-3( 2H l O-dione.

3. The compound according to claim 1 wherein R is pbromophenyl;2-(p-bromophenyl)-l ,4,4a,9b-tetrahydro-8,9bdimethyll,4-ethanobenzofuro[3,2-c]pyridine-3( 2H, 1 0- dione.

4. A compound of the formula:

wherein R and R are the same and are each selected from the groupconsisting of phenyl and pbromophenyl.

5. The compound according to claim 4 wherein R and R are both phenyl;1,2,3,4,4a,9bhexahydro-8,9b-dimethyl- 3,10-dioxo-2-phenyl-l,4-ethanobenzofuro[ 3 ,2-c]pyridinel l carboxanilide.

6. The compound according to claim 4 wherein R and R are bothp-bromophenyl; 4'-bromo-2-(p-bromophenyl)- 1,2,3,4,-4a,9b-hexahydro-8,9b-dimethyl-3 l O-dioxol ,4- ethanobenzofuro-[3,2-c]pyridine-1 l-carboxanilide.

7. A compound of the formula:

0 CH3 /W l wm wherein R 5561 are the same and are each selected from thegroup consisting of phenyl and p-bromophenyl.

8. The compound according to claim 7 wherein R and R are both phenyl;l,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3- oxo-2-phenyll 0-(1-pyrrolidinyl)-1,4-ethenobenzofuro[3,2-

c pyridine-1 l-carboxanilide.

9. The compound according to claim 7 wherein R, and R are bothp-bromophenyl; 4'-bromo-2-(p-bromophenyl)-1,2,3,4,-4a,9b-hexahydro-8,9b-dimethyl-3-oxol 0-( l-pyrrolidinyl l,4-ethenobenzofuro[3,2-c1pyridinel l-carboxanilide.

2. The compound according to claim 1 wherein R is phenyl; 1,4,4a,9b-tetrahydro-8,9b-dimethyl-2-phenyl-1,4-ethanobenzofuro(3,2-c)pyridine-3(2H),10-dione.
 3. The compound according to claim 1 wherein R isp-bromophenyl;2-(p-bromophenyl)-1,4,4a,9b-tetrahydro-8,9b-dimethyl-1,4-ethanobenzofuro(3,2-c)pyridine-3(2H,10-dione.4. A compound of the formula:
 5. The compound according to claim 4wherein R1 and R2 are both phenyl;1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3,10-dioxo-2-phenyl-1,4-ethanobenzofuro(3,2-c)pyridine-11-carboxanilide.
 6. The compoundaccording to claim 4 wherein R1 and R2 are both p-bromophenyl;4''-bromo-2-(p-bromophenyl)-1,2,3,4,-4a,9b-hexahydro-8,9b-dimethyl-3,10-dioxo-1,4-ethanobenzofuro-(3,2-c)pyridine-11-carboxanilide.7. A compound of the formula:
 8. The compound according to claim 7wherein R1 and R2 are both phenyl;1,2,3,4,4a,9b-hexahydro-8,9b-dimethyl-3-oxo-2-phenyl-10-(1-pyrrolidinyl)-1,4-ethenobenzofuro(3,2-c)pyridine-11-carboxanilide.9. The compound according to claim 7 wherein R1 and R2 are bothp-bromophenyl;4''-bromo-2-(p-bromophenyl)-1,2,3,4,-4a,9b-hexahydro-8,9b-dimethyl-3-oxo-10-(1-pyrrolidinyl)-1,4-ethenobenzofuro(3,2-c)pyridine-11-carboxanilide.